Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia

Nat Immunol. 2015 Jul;16(7):766-774. doi: 10.1038/ni.3160. Epub 2015 May 18.

Abstract

Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.

MeSH terms

  • Adolescent
  • Animals
  • Antibody Diversity / genetics
  • Antibody Diversity / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Child
  • Child, Preschool
  • Clonal Evolution / genetics
  • Clonal Evolution / immunology*
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / immunology
  • Cytidine Deaminase / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Female
  • Flow Cytometry
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunoblotting
  • Infant
  • Male
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cells, B-Lymphoid / immunology*
  • Precursor Cells, B-Lymphoid / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Homeodomain Proteins
  • V(D)J recombination activating protein 2
  • RAG-1 protein
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase